PROJECT 4 - Abstract Given the reality that human infants can be exposed to stressors and antidepressant drugs in utero as part of life events or appropriate medical treatment of the mother, the long term developmental consequences on the offspring need to be determined as one aspect of planning and monitoring long term health issues. This project focuses upon the biological consequences (biochemical, molecular, physiological and genetic) of the quality of maternal care interacting with prenatal stress and in utero antidepressant exposure on brain function of offspring when these rats become adults of reproductive age (i.e., does prenatal exposure to these factors alter the long term biology of the brain?). This project will focus on three unique aspects of adult brain function. 1) What are the regional brain neurochemical and molecular changes that result (the markers to be examined have all been previously promulgated, but not tested, to be involved in stress responsivity or the mechanisms of action of antidepressants) from maternal care, prenatal stress exposure, and in utero antidepressant exposure? 2) Are there structural changes in the microvascular system supplying blood to the brain or in the angiogenic growth factors that signal new blood vessel formation and retraction? For example, although.it is well established that CMS plasticity includes changes in synaptic morphology, neuronal connectivity, glial morphology and function as well as changes in vasculature, the effects of maternal care, early life stressors, and in utero antidepressant treatment on the CNS have only been addressed for neurons and glia. 3) We will attempt to identify genetic loci that are epigenetically altered by the quality of maternal care, prenatal stress, and in utero exposure to antidepressants in rat brains. We will use ChlP-on-chip technology to investigate how the quality of maternal care, prenatal stress, and in utero exposure to SSRI's alter the epigenetic profiles (both DNA methylation and histone modification) of the promoter regions across the genome in rat brains at birth and in adulthood. In addition, the mRNA expression profiles from the same brain regions will be evaluated and correlated with the epigenetic profiles. These state-of-the-art techniques can offer unique insight into the long term changes, or lack thereof, produced by differences in maternal care, prenatal stress, and in utero antidepressant exposure.